There is a growing interest in the use of chronic deep brain stimulation (DBS) for the treatment of medically refractory movement disorders and other neurological and psychiatric conditions. Fundamental questions remain about the physiologic effects of DBS. It is also unclear what stimulation parameters are optimal for the present or future uses of DBS. Previous basic research studies have focused on the direct polarization of neuronal membranes by electrical stimulation. The proposal aims to determine if DBS can indirectly affect brain function (neuronal polarization) through: 1) joule heating of tissue; or 2) electro-permeation of the blood-brain barrier. It is well established that electric current can induce tissue heating and membrane electroporation; however, it remains unclear if the electric fields induced during clinical DBS are sufficient to induce these effects. The overall goal of the proposal is to determine the potential scale of DBS induced temperature and permeability changes by using a bio-heat transfer model and an in vitro endothelial barrier model, respectively. Even small and transient changes in brain temperature or blood-brain barrier permeability can have profound effects on neuronal function and hence on DBS efficacy or safety. This study will provide the-first insight into the role of these novel 'indirect' DBS mechanisms and thus advance improvements in clinical DBS protocols/technology. Relevance to Public Health: Deep Brain Stimulation (DBS) is a highly promising technology for the treatment of neurological disorders such as Parkinson's disease and tremor. This proposal will determine if Deep Brain Stimulation is affecting brain function by raising local temperature or changing the permeability of the blood- brain barrier. These results will improve the success and safety of DBS. [unreadable] [unreadable] [unreadable]